Capsules

ABSTRACT

Capsules, for example for the delivery of pharmaceuticals, are produced from two films ( 18 ) of a water-soluble polymeric material, by deforming the films to form a multiplicity of recesses, and filling the recesses with a flowable filling material. This is performed using two adjacent rotary dies ( 14, 15 ), with recesses ( 16 ) into which the films ( 18 ) are deformed. The dies ( 14, 15 ) also act as electrodes for welding the films together by dielectric welding to form filled capsules ( 30 ). The capsules ( 30 ) can readily be separated from the resulting web. The polymeric material may be gelatin, or a water-soluble cellulose derivative such as hydroxypropyl methyl cellulose, and may also contain a plasticiser.

[0001] This invention relates to a process and an apparatus for formingcapsules, for example for the delivery of pharmaceuticals, and also tothe resulting capsules.

[0002] A variety of pharmaceuticals and other materials are delivered incapsules. Where the material is a particulate material such as a powderit may be enclosed in a hard capsule, typically of elongated round-endedcylindrical shape, made in two pieces for assembly around the material.Both liquid and particulate material may be enclosed in soft capsules,these capsules being made from films of a soft elastic polymer which arebrought together between rotating dies that have cavities in theirsurfaces. The material to fill the capsules is supplied between thefilms as the films deform into the cavities; as the dies move the filmscome together and are sealed together by application of heat and/orpressure at the dies. Both types of capsules are commonly made fromgelatin films. The bonding of thermoplastic polymer films usingdielectric heating (or radio frequency heating) has also been known formany years. In this process the two pieces of thermoplastic material arepositioned between opposed electrodes (or one electrode and a baseplate), the electrodes are pressed together, and a radio frequencyvoltage is applied between the electrodes. This process is howeverapplicable only to those materials which have a significant dielectricloss index, for example greater than 0.2, over the range say 20-60 MHz,for example polyvinylchloride. Dielectric welding has not hitherto beenconsidered suitable for welding the water-soluble polymers which aredesirably used in making capsules for pharmaceuticals.

[0003] According to the present invention there is provided a processfor making capsules, the process using two films of a water-soluble ordigestible polymeric material, and the process comprising the steps ofdeforming the films to form a multiplicity of recesses between a pair ofrotary dies, filling the recesses with a flowable filling material,welding the films together by dielectric welding at the rotary dies toform a multiplicity of enclosures containing the filling material, andseparating the filled enclosures from the remaining parts of the filmsso as to form a multiplicity of capsules.

[0004] The rotary dies act as opposed electrodes, to which the highfrequency electrical supply is provided. The supply may in principle beat a frequency between 1 MHz and 200 MHz, usually between 10 MHz and 100MHz, but stringent limits are imposed on any emitted radio waves. Inpractice therefore the choice of frequency may be more limited. Forexample the supply frequency may be 27.12 MHz, or 40.68 MHz. Preferablythe electrical connections to both the rotary dies are by a capacitativecoupling. Alternatively the coupling may be by a sliding contact, forexample with brushes. A tuned circuit may be electrically connected toat least one of the electrodes, for example the tuned circuit may beconnected between one electrode and ground potential. For example atuned circuit may comprise an inductor connected to the capacitativecoupling to one electrode and to ground potential, the tuned circuitpreferably resonating at a frequency substantially that of the supply.The tuned circuit may be a matching network.

[0005] Each rotary die may be substantially cylindrical, and rotateabout a fixed axis of rotation. Alternatively each rotary die may be ofsubstantially polygonal cross-section, for example octagonal, the axesof rotation being sprung loaded towards each other. The dies may bearranged to form one capsule at a time, forming the multiplicity ofrecesses in succession as the dies rotate. Alternatively the dies may bearranged to form a plurality of capsules at once, side-by-side acrossthe width of the films. A heater may be associated with the rotary dies,to provide heating of the films to soften them, before they are deformedto form the recesses. The films may be deformed by suction into matchingrecesses in the dies. The cutting out of the capsules may be performedby punching, but alternatively the dies may be sufficiently closetogether, at least around the periphery of each recess, that the filmsurrounding each capsule is sufficiently thin that the capsules can beeasily pushed out of the remaining web; for example around the peripheryof each capsule the film might be of a thickness between 10 and 20 μm.

[0006] The filling material may be a pharmaceutical, and is a preferablya liquid. Where the capsules are intended to be swallowed (for examplewhere they contain a pharmaceutical or a nutritional supplement), thepolymeric material should be ingestible. It may for example be gelatin,or a water-soluble cellulose derivative. For example it may behydroxypropyl methyl cellulose, which is approved for use withpharmaceuticals and in food (being indicated by the code E464 inEurope). Other suitable polymeric materials would be edibleseaweed-derived polymers such as sodium alginate (E401), propyleneglycol alginate (E405) or agar-agar (E406). The polymeric material mustnot contain any harmful or toxic additives, but may contain compoundssuch as glycerol (E422) or glycerol monostearate (E471) as plasticisers,these compounds also being ingestible and dispersible or soluble inwater. Other suitable cellulose derivatives are hydroxypropyl cellulose(E463), and methyl ethyl cellulose (E465). There is no requirement forany water to be added to the film, and indeed it is preferable that thefilms should be at least superficially dry, that is to say inequilibrium with ambient conditions. For example the film might be inequilibrium with air at a temperature of 25° C. and a relative humidityof 40%. For example, it might be stored before use in a controlledhumidity environment, with a relative humidity preferably in the range30% to 70%. Under such circumstances the film would evidentlyincorporate some water but would appear completely dry, and suchincorporated water would tend to act as a plasticiser.

[0007] The invention also provides an apparatus for making and fillingcapsules by the method specified above, comprising rotary dies arrangedto deform the film and to dielectrically weld them together. In afurther aspect, the invention provides a capsule formed by the method orapparatus of the invention.

[0008] The invention will now be further and more particularlydescribed, by way of example only, and with reference to theaccompanying drawing which shows a side view, partly in section, of anapparatus for forming capsules.

[0009] Referring to FIG. 1 this shows schematically an apparatus 10 formaking capsules of an ingestible, pharmaceutical grade material, such ashydroxypropyl methyl cellulose, the capsules being filled with anon-aqueous liquid filling material 12. The apparatus comprises twoadjacent rotary dies 14 and 15, each of generally cylindrical externalshape, which define a plurality of oval recesses 16 in their periphery(eight recesses, as shown, along a peripheral path), the rotations ofthe dies 14 and 15 being synchronized so that the recesses 16 are alwaysopposite each other. Heaters (not shown) are arranged to maintain thedies 14 and 15 at a temperature between 50 and 70° C., for example 60°C. Two sheets 18 of the polymeric material (hydroxypropyl methylcellulose containing glycerol ester as a plasticiser in this example)are supplied to the dies 14 and 15 from rollers 20, each sheet 18 beingof uniform thickness 0.20 mm. The dies 14 and 15 are of the same lengthas the width of the films 18, and may have other sets of recesses spacedaxially along their length, for example six. The dies 14 and 15 arehollow, defining within them narrow ducts (not shown) communicating withthe base of each recess 16, and valves (not shown) whereby suction canbe applied to those recesses 16 that are immediately above the pinchbetween the dies 14 and 15. The axes of rotation of the dies 14 and 15are spring loaded towards each other, so the films 18 are subjected tocompression as they pass between the dies 14 and 15, and are arranged sothat, at their closest, the dies are 12 μm apart immediately around eachrecess 16.

[0010] Immediately above the two dies 14 and 15 is a non-conductiveguide block 22, the films 18 passing between the lower curved surface ofthe guide block 22 and the outer surface of the dies 14 and 15. Thefilling material 12 is fed through ducts 24 in the guide block 22 intothe gap between the films 18 just above the point where they cometogether, each duct 24 being aligned with one of the sets of peripheralrecesses 16. The films 18 are softened by their contact with the heatedsurface of the dies 14 or 15, and are deformed by being sucked into therecesses 16 above the pinch point. Hence the filling material 12 fillsthe recesses 16 at this point.

[0011] A high frequency generator 26 is connected via a capacitativecoupling 27 to the die 15, this generating an electrical current at afrequency of 27.12 MHz. The other die 14 is connected via anothercapacitative coupling 28 and an inductor 29 to earth potential. Thecapacitative coupling 28 and the inductor 29 together form a tunedcircuit that has a resonant frequency at which its impedance is aminimum, the value of the inductor being selected so the resonantfrequency is at (or close to) the frequency of the generator 26. Inoperation of the apparatus 10 the generator 26 continuously suppliesthis high frequency signal, so that as the films 18 pass between thedies 14 and 15 they are subjected to dielectric welding. The opposedfaces of the sheets 18 become hot enough to fuse together, whereas theouter faces in contact with the dies remain at the temperature of thedies 14 and 15. Thus in operation an array of filled capsules 30, eachsealed and connected together by a web of welded sheet 18, emerges frombelow the rotary dies 14 and 15. The web is only 12 μm thick around theperiphery of each capsule 30, so that the capsules 30 can readily beseparated from the remainder of the web.

[0012] Because the polymeric material melts during the welding process,a bead of molten material forms around the the welded seam on the insideof each capsule 30, so that after the capsules have been cut out thewall thickness is slightly thicker around the seam. The sealed nature ofthe capsules 30 allows the material 12 to be liquid, so that a widerange of pharmaceuticals can be delivered with such a capsule 30. By wayof example each capsule 30 might be of ellipsoidal shape, 10 mm long and7 mm wide. The use of a cellulose derivative (such as hydroxypropylmethyl cellulose) for the sheets 18, and so for the walls of thecapsule, has advantages in view of the proven use of such material forpharmaceutical applications, and in view of its solubility in water andits lack of toxic effects.

[0013] The solubility of the capsule walls means that the capsules willbreak down quickly in a patient's stomach, giving rise to a fast releaseof the pharmaceutical. For some applications the speed of release may beexcessively fast. In that case, or for aesthetic reasons or reasons oftaste and handling, the capsules might be embedded in additionalmaterial such as a sugar coating for improved taste, or a less solublecoating to slow down release.

[0014] It is apparent from the description of the welding arrangements,that direct contact is made between the dies 14 and 15 and the sheets 18of material being welded. Barrier sheets commonly used in dielectricwelding are not required or used. This increases the acceptability ofthe process for pharmaceutical use, in avoiding the use of a potentialsource of contamination, particularly in view of the fibrous nature ofcommon barrier materials. A particular advantage of the presentinvention is that the capsules 30 can be filled with liquid. The liquidmay be a solution of a pharmaceutically active material, or a medicinein liquid form, or an emulsion of pharmaceutical material in a liquid,or a pharmaceutically active oil or other liquid. It will be readilyunderstood that the filling material 12 must be compatible with thematerial of the sheet 18 and in particular that water and aqueoussolutions are not desirable in view of the highly soluble nature of thecellulose derivative. The filling material might alternatively be afree-flowing powder, for example.

[0015] Many variations and modifications may be made to the apparatusdescribed above without departing from the scope of the presentinvention. For example three sheets might be welded together in a singleoperation, with recesses in the outer sheets, so that a two-compartmentcapsule could be produced in which each compartment held a differentmaterial. Pharmaceutical grade cellulose derivatives are highlypreferred, but other materials such as gelatin may be used. In any eventthe presence of a plasticiser in the polymer film is beneficial to boththe formation of the recesses and the welding process. The rotary diesmay compress the films down to a thickness of say 0.3 mm over the entireweld area, so that in the welding process molten polymer will tend toflow so as to create a bead of molten material around the welded seam atthe edge of each recess. The rotary dies might incorporate a punchmechanism to separate the capsules 30 from the web, rather than merelyforming a thin portion of web around each capsule 30.

1. A process for making capsules from films (18) of polymeric material,the process comprising the steps of deforming the films (18) to form amultiplicity of recesses (16), filling the recesses (16) with a flowablefilling material (12), welding the films together to form a multiplicityof enclosures (30) containing the filling material (12), and separatingthe filled enclosures (30) from the remaining parts of the films (18) soas to form the said multiplicity of capsules, wherein the weldingprocess is dielectric welding performed between a pair of rotary dies(14, 15), and characterized in that the process uses films (18) of awater-soluble or digestible polymeric material.
 2. A process as claimedin claim 1 wherein the dielectric welding step involves applyingelectrical signals to the rotary dies (14, 15) by use of capacitativecouplings (27, 28).
 3. A process as claimed in claim 1 or claim 2wherein the electrical connection to at least one rotary die (14)incorporates a tuned circuit (28, 29).
 4. A process as claimed in anyone of the preceding claims wherein each film (18) comprises awater-soluble cellulose derivative.
 5. A process as claimed in any oneof the preceding claims wherein each film (18) comprises a water-solubleor digestible plasticiser.
 6. A process as claimed in any one of thepreceding claims wherein each film (18) is dry, being in substantialequilibrium with ambient atmosphere containing humidity.
 7. A process asclaimed in any one of the preceding claims wherein the films (18) areheated to above ambient temperature before being deformed to form therecesses.
 8. A process as claimed in any one of the preceding claimswherein the dies (14, 15) are sufficiently close together during thewelding process, at least around the periphery of each recess (16), thatafter welding the film surrounding each capsule (30) is sufficientlythin that the capsules (30) can be easily separated from the remainingweb.